PROJECT SUMMARY Toxic metals including cadmium (Cd), mercury (Hg), and lead (Pb) are known renal toxicants in adults; however, their renal toxicity in developing children is understudied. Prenatal and early childhood are potential susceptibility windows for renal toxic metals as these life stages are associated with development and differentiation of renal filtration, secretion, and reabsorptive systems. The aim of this study is to determine whether exposure to heavy metals early in life contributes to renal toxicity in children and whether miRNAs mediate metal nephrotoxicity. To accomplish our goals, we will leverage an established longitudinal birth cohort in Mexico City - the Programming Research in Obesity, GRowth Environment and Social Stress (PROGRESS) study, which has measured levels of renal toxic metals (Cd, Hg, Pb) longitudinally in blood, hair, and nails as well as blood pressure, and collected urine at each visit. In addition to childhood blood pressure, the proposed research will examine preclinical indicators of renal dysfunction in three discrete regions of the kidney: the glomerulus, proximal tubule and distal nephron (i.e. distal tubule and collecting duct). Dr. Sanders will receive training in renal developmental physiology, as well as advanced biostatistical methods to address innovative hypotheses regarding the origins of toxic renal programming in children, an understudied aspect of environmental health. The mentoring team includes internationally recognized scientists with specializations in nephrology, biostatistics, metals toxicology, epidemiology, and epigenetics, including Dr. Lisa Satlin, Dr. Chris Gennings, Dr. Robert Wright, Dr. Andrea Baccarelli, and Dr. Stephanie Engel. This K99/R00 proposal leverages Dr. Sanders' previous training in exposure science, epidemiology, and epigenetics with new specialization in renal physiology and biostatistics; Dr. Sanders will also benefit from supplemental toxicology and clinical training. The following aims will be accomplished: 1) Determine whether prenatal/early life metal exposure predicts childhood blood pressure or functional biomarkers in specific kidney regions. 2) Apply a novel biostatistical approach to enable ?detection? of metal-associated renal toxicity that is global or site- specific. 3) Examine the role of urinary miRNAs as biomarkers/mediators of metal-renal health relationships. These findings will advance the field of children's renal health as well as generate new hypotheses about metals and specific mechanisms that may contribute to the pathophysiology of adverse renal outcomes. The proposed training and research activities will provide Dr. Sanders with the skills to become an independent investigator studying early life metal exposure and renal development in future epidemiologic or toxicologic research activities.